All patients with persistent, nonspecific musculoskeletal pain are at high risk for the consequences of unrecognized and untreated severe hypovitaminosis D.

Because osteomalacia is a known cause of persistent, nonspecific musculoskeletal pain, screening all outpatients with such pain for hypovitaminosis D should be standard practice in clinical care.

Of the many types of chronic pain, nonspecific or idio- pathic musculoskeletal pain, such as noninflammatory arthritis, nonarticular rheumatism, and nonradicular low back pain, is seen frequently in medical and chiropractic clinics. Despite the prevalence, severity, and burdens of such pain, precise diagnosis and effective treatment are often elusive.

Unexpectedly, 100% of Af- rican American (n=22), 100% of American Indian (n=10), and 83% (29/35) of white patients with persistent pain also had hypovitaminosis D (mean, 11.7 ng/mL; 95% CI, 10.17- 13.27 ng/mL).

More than 90% of the patients in this study with persistent, nonspecific musculoskeletal pain were found to have deficient levels of 25-hydroxyvitamin D. Mean values were in the moderately severe to moderately deficient range. This was true regardless of immigrant status, sex, race, or season.

Even oral supplementation with vitamin D tablets may be inadequate at currently recommended doses.44-46 Up to 46% of persons found to be vitamin D–deficient have met the recommended daily intake.47-49 Also, oral supplements may not provide sufficient compensation for patients with existing hypovitaminosis D.50,51

These results support screening of all outpatients with persistent, nonspecific musculoskeletal pain for hypovitaminosis D. These patients are at high risk for the consequences of unrecognized and untreated hypovitaminosis D, and this risk extends to those now considered at low risk, including nonelderly, nonhousebound, or nonimmigrant persons of either sex

Vitamin D deficiency causes muscle weakness and muscle aches and pains in both children and adults. Glerup et al8 reported that 88% of Danish women of Arab descent who presented with muscle pains and weakness were se- verely vitamin D–deficient. Bischoff et al9 observed that adults with vitamin D deficiency have muscle weakness and are more likely to fall.

Heaney et al14 estimated that the body uses 3000 to 5000 IU/d of vitamin D. What does the body do with all that vitamin D? Most organs in the body, including the brain, heart, pancreas, skin, and immune system, recog- nize 1,25-dihydroxyvitamin D.2,7 Furthermore, many of these organs also have the capacity to make 1,25- dihydroxyvitamin D.2,7 Besides regulating calcium homeo- stasis, 1,25-dihydroxyvitamin D is a potent inhibitor of cellular growth, stimulator of insulin secretion, modulator of immune function, and inhibitor of renin production.2,7 These functions are likely responsible for the numerous epidemiological observations that people who live at higher latitudes and who are more prone to vitamin D deficiency are at increased risk of developing prostate, colon, breast, and other solid tumors15; autoimmune dis- eases including multiple sclerosis and type 1 diabetes; hy- pertension; and cardiovascular heart disease.2,7

Vitamin D deficiency can be treated easily by giving the patient an oral dose of 50,000 IU of vitamin D once a week for 8 weeks.16 Long-term prevention of vitamin D defi- ciency can be accomplished by giving 50,000 IU of vitamin D once or twice a month.

«With the advent of the agricultural and industrial revolutions, we have introduced numerous false inflammatory triggers in our lifestyle, driving us to a state of chronic systemic low grade inflammation that eventually leads to typically Western diseases via an evolutionary conserved interaction between our immune system and metabolism. The underlying triggers are an abnormal dietary composition and microbial flora, insufficient physical activity and sleep, chronic stress and environmental pollution. «

«Our brain consumes 20–25%2 of our basal metabolism [11], [12], [13], [14], [15], [16], [17] and [20] and is thereby together with the liver (19%2), our gastrointestinal tract (15%2), and skeletal musculature (15%2) among the quantitatively most important organs in energy consumption [19].»

«There is a linear relationship between body weight and basal metabolism among terrestrial mammals (Fig. 2). This apparently dogmatic relationship predicts that, due to the growth of our brain, other organs with high energy consumption had to be reduced in size, what in evolution is known as a “trade-off”.3 As a consequence of this “expensive tissue hypothesis” of Aiello and Wheeler [19], our intestines, amongst others, had to become reduced in size. «

«A glucose deficit leads to competition between organs for the available glucose. As previously mentioned, this occurs during fasting, but also during pregnancy and infection/inflammation. « «During competition between organs for glucose, we fulfill the high glucose needs of the brain by a reallocation of the energy-rich nutrients, and to that end, we need to become insulin resistant.»

» For example, the concomitant hypertension has been explained by a disbalance between the effects of insulin on renal sodium reabsorption and NO-mediated vasodilatation, in which the latter effect, but not the first, becomes compromised by insulin resistance, causing salt sensitivity and hypertension [54].»

«However, it becomes increasingly clear that we could better refer to it as the “chronic systemic low-grade inflammation induced energy reallocation syndrome”. The reason for this broader name derives from the recognition that insulin resistance is only part of the many simultaneously occurring adaptations. To their currently known extent, these adaptations and consequences are composed of:
(i) reduced insulin sensitivity (glucose and lipid redistribution, hypertension),
(ii) increased sympathetic nervous system activity (stimulation of lipolysis, gluconeogenesis and glycogenolysis),
(iii) increased activity of the HPA-axis [hypothalamus-pituitary-adrenal gland (stress) axis, mild cortisol increase, gluconeogenesis, with cortisol resistance in the immune system],
(iv) decreased activity of the HPG-axis (hypothalamus-pituitary-gonadal gland axis; decreased androgens for gluconeogenesis from muscle proteins, sarcopenia, androgen/estrogen disbalance, inhibition of sexual activity and reproduction),
(v) IGF-1 resistance (insulin-like growth factor-1; no investment in growth) and vi) the occurrence of “sickness behavior” (energy-saving, sleep, anorexia, minimal activity of muscles, brain, and gut) [3].»

«Summarizing thus far, we humans are extremely sensitive to glucose deficits, because our large brain functions mainly on glucose. During starvation, pregnancy and infection/inflammation, we become insulin resistant, along with many other adaptations. «

«The metabolic adaptations caused by inflammation illustrate the intimate relationship between our immune system and metabolism. This relation is designed for the short term. In a chronic state it eventually causes the metabolic syndrome and its sequelae. We are ourselves the cause of the chronicity. Our current Western lifestyle contains many false inflammatory triggers and is also characterized by a lack of inflammation suppressing factors. These will be described in more detail below.»

«Among the pro-inflammatory factors in our current diet, we find:
– the consumption of saturated fatty acids [82] and industrially produced trans fatty acids [83] and [84], a high ω6/ω3 fatty acid ratio [85], [86] and [87],
– a low intake of long-chain polyunsaturated fatty acids (LCP) of the ω3 series (LCPω3) from fish [88] and [89],
– a low status of vitamin D [90], [91] and [92], vitamin K [93] and magnesium[94], [95] and [96],
– the “endotoxemia” of a high-fat low-fiber diet [97] and [98],
– the consumption of carbohydrates with a high glycemic index and a diet with a high glycemic load [99] and [100],
– a disbalance between the many micronutrients that make up our antioxidant/pro-oxidant network [101], [102] and [103], and
– a low intake of fruit and vegetables [103] and [104].
The “dietary inflammation index” of the University of North Carolina is composed of 42 anti- and proinflammatory food products and nutrients. In this index, a magnesium deficit scores high in the list of pro-inflammatory stimuli [105]. Magnesium has many functions, some of them, not surprisingly, related to our energy metabolism and immune system, e.g., it is the cation most intimately connected to ATP [95].
Indirect diet-related factors are
– an abnormal composition of the bacterial flora in the mouth [106], gut [106] and [107], and gingivae [108], [109] and [110].
– Chronic stress[111] and [112],
– (passive) smoking and
– environmental pollution [77],
– insufficient physical activity [113],[114], [115], [116], [117] and [118] and
– insufficient sleep [119], [120], [121], [122] and [123] are also involved.»

«Diets high in refined starches, sugar, saturated and trans fats, and low in LCPω3, natural antioxidants, and fiber from fruits and vegetables, have been shown to promote inflammation [82], [83], [84], [129],[130] and [131] (Table 1).»

«Molecular oxygen is essential to aerobic life and, at the same time, an oxidizing agent, meaning that it can gain electrons from various sources that thereby become “oxidized,” while oxygen itself becomes “reduced”[252] and [253]. In general terms, an antioxidant is “anything that can prevent or inhibit oxidation” and these are therefore needed in all biological systems exposed to oxygen [252].»
«The emergence of oxygenic photosynthesis and subsequent changes in atmospheric environment [254] forced organisms to develop protective mechanisms against oxygen’s toxic effects [255]. »

» Damage by oxidation of lipids[262], [265] and [266], nucleic acids and proteins changes the structure and function of key cellular constituents resulting in the activation of the NFκB pathway, promoting inflammation, mutation, cell damage and even death [252], [260] and [267] and is thereby believed to underlie the deleterious changes in aging and age-related diseases [102] and [244].»

»
Fig. 8. Antioxidant defense mechanisms. An overview of the antioxidant system present in the human body. Various types of antioxidant systems have developed through time, reflecting different selection pressures. Different forms have developed for the same purpose, for example, SODs, peroxidases and GPx are important members of the antioxidant enzyme capacity group. Tocopherols and ascorbic acid, as representatives of the antioxidant network, are manufactured only in plants, but are needed by animals. Ascorbic acid is an essential antioxidant, but cannot be synthesized by Homo sapiens. In humans, therefore, antioxidant defense against toxic oxygen intermediates comprises an intricate network which is heavily influenced by nutrition. GR, glutathione reductase; GSG, reduced glutathione; GSH-Px, glutathione peroxidase; GSSG, oxidized glutathione; GST, glutathione-S-transferase; MSR, methionine sulphoxide reductase; PUFA, polyunsaturated fatty acids; S-AA, sulphur amino-acids; SH-proteins, sulphydryl proteins; SOD, superoxide dismutase; Fe Cu, transition metal-catalysed oxidant damage to biomolecules.»

«A certain level of ROS may also be essential to trigger antioxidant responses [276].»

«Chronic inflammation results in the chronic generation of free radicals, which may cause collateral damage and stimulate signaling and transcription factors associated with chronic diseases [294] and [295].»

«Our diet is composed of millions of substances that are part of a biological network. In fact, we eat “biological systems” like a banana, a fish or a piece of meat. There is a connection between the various nutrients in these systems. In other words, there is a balance and an interaction that is part of a living organism. »

«As clearly explained by Rose[328]: «If everyone smoked 20 cigarettes a day, then clinical, case–control and cohort studies alike would lead us to conclude that lung cancer was a genetic disease; and in one sense that would be true, since if everyone is exposed to the necessary agent, then the distribution of cases is wholly determined by individual susceptibility”. In other words: “disease susceptibility genes” is a misnomer from an evolutionary point of view.»

«Hemminki et al.[326] stated that “if the Western population was to live in the same conditions as the populations of developing countries, the risk of cancer would decrease by 90%, provided that viral infections and mycotoxin exposures could be avoided”.»

«It has become clear that most, if not all, typically Western chronic illnesses find their primary cause in an unhealthy lifestyle and that systemic low grade inflammation is a common denominator.»